Bipolar disorder (BD) is a life-threatening mental illness that affects 1-2% of the population, including ~100,000 veterans. In responsive patients, lithium is an excellent treatment for BD, but many patients fail to respond and needlessly suffer side-effects or delays from unsuccessful treatment or misdiagnosis. Therefore new techniques to rapidly diagnose BD and identify lithium responders would be of clinical utility. Lithium has several biological effects. Among these, it alters gene expression and circadian rhythms, including those disrupted in BD. The circadian clock is comprised of an interacting network of genes that maintain rhythms over ~24 hr cycles. While the suprachiasmatic nucleus of the hypothalamus is the master clock for circadian rhythms, clock genes are functional in peripheral tissues and can be studied in cultured skin cells (fibroblasts). We have employed specialized reporter genes to facilitate these studies. Reporters can be inserted into cultured cells where they can be used to study circadian rhythms over several days by measuring bioluminescence. Using this approach, one can accurately study the circadian clock in tissues from BD patients. Circadian rhythms studies may provide insights into how lithium works to treat BD. By understanding lithium's actions it may be possible to develop predictors of treatment response, or to develop new medications. The work proposed for this career development award (CDA2) aims to identify: 1) Variants in clock genes that influence lithium response 2) Effects of genetic variants on clock function and 3) The locus of lithium's action within the clock. I will employ two methods to address these questions: 1) Measure gene expression using bioluminescent reporter genes in cell cultures from BD patients and 2) Perform genetic association studies in lithium-treated BD patients. The applicant is a post-doctoral fellow in biological psychiatry with both M.D. and Ph.D. (Neuroscience) degrees. The short-term goal of this CDA2 will be complete his transition from clinical training to translational research independence. By studying how clock genes malfunction in BD, and how lithium interacts with them, he will get additional training in advanced concepts and techniques in genetics and neurobiology. In order to meet the training goals, a detailed plan incorporating general and specialized activities has been developed. These include didactic and applied problem-based approaches that are supported by the proposed research activity. The co-mentors for the CDA2 are Drs Kelsoe and Welsh, recognized experts in psychiatric genetics and circadian rhythms respectively. The applicant will also receive additional training from Drs Dunn, Gage and Ideker who will oversee training in ethics of genetic testing, stem-cell based models of BD, and bioinformatic analysis of genetic interactions. The work will be conducted within the San Diego VA Healthcare System, in affiliation with UCSD, an academic center recognized for its strengths in psychiatric genetics, neurobiology and chronobiology. With these added skills, the applicant's long-term goal is to develop expertise in the molecular genetics of mood disorders and function as a physician-scientist to develop biologically-based approaches to treating the mentally ill; an approach that has historically shown to yield results in improved treatment in other fields of medicine.